Adcetris: genotox, carcinogenicity and repro: done or skipped?

“MMAE was genotoxic in the rat bone marrow micronucleus study through an aneugenic mechanism.”

“Carcinogenicity studies with brentuximab vedotin or the small molecule (MMAE) have not been conducted.”

“In rats, brentuximab vedotin was clearly embryo-foetal toxic, causing loss of almost all embryos at 3 mg/kg and above.”

“In a dedicated safety pharmacology study in cynomolgus monkeys a single IV infusion of brentuximab vedotin up to 3 mg/kg had no effect on the cardiovascular, respiratory or central nervous systems.”

“MMAE was not mutagenic in the bacterial reverse mutation assay (Ames test) or the L5178Y mouse lymphoma forward mutation assay.”

“MMAE was not mutagenic in the bacterial reverse mutation assay (Ames test) or the L5178Y mouse lymphoma forward mutation assay.”

“MMAE was genotoxic in the rat bone marrow micronucleus study through an aneugenic mechanism.”

“No carcinogenicity studies, fertility and early embryonic development studies and prenatal or postnatal studies (including maternal function) or studies in which the offspring (juvenile animals) are further dosed and evaluated were submitted, which is acceptable as brentuximab vedotin is intended for the treatment of patients with relapsed or refractory HL and sALCL.”

“No carcinogenicity studies, fertility and early embryonic development studies and prenatal or postnatal studies (including maternal function) or studies in which the offspring (juvenile animals) are further dosed and evaluated were submitted, which is acceptable as brentuximab vedotin is intended for the treatment of patients with relapsed or refractory HL and sALCL.”

“With regard to safety pharmacology, MMAE produced a fractional block of peak hERG tail current that was significantly different from the negative control at high MMAE concentration (100 µM) but not at the low concentration (10 µM).”